This proposal is designed to investigate the immunogenetic basis for susceptibility to development of acute and chronic relapsing experimental allergic encephalomyelitis (EAE) in mice. Our intention is to use radiation chimera and adoptive transfer protocols between low and high EAE responder mice of normal and recombinant inbred strains to analyze the immuno- pathological level at which non-MHC genes may contribute of the control of the disease process. With the additional use of heterotopic brain tissue transplants we will be able to assess whether susceptibility to EAE is at the level of immune responsiveness, antigen presentation in the periphery, the ability to penetrate the blood-brain barrier, or related to the CNS target tissue, itself. A second series of experiments will concentrate on the relative significance of H-2 Ia determinant recognition by L3T4+ T cells for the induction and effector phases of EAE. This question can be approached by manipulation of permissive Ia expression, again by means of radiation chimeric mice. The third and final emphasis of this study is to evaluate the immunological relevance of T cell subsets, including L3T4+ (helper-type), LYT 2+ (cytotoxic/suppressor-type), and those cells responsible for contrasuppression, in the development of EAE. Related to this question is whether we can monitor CNS-responsive T cells in the recirculating lymphocyte pool after stimulation and develop approaches to specifically deplete them. The overall aim of these experiments involving EAE is to gain some possible insights into an understanding of the nature of multiple sclerosis and potential approaches to better diagnosis and therapy.